Constructing a Transgenic Mouse Model Based On SLC25A12, MARK1 and PRKCB1 Gene Dosage Imbalance Mimicking Gene Expression Changes Found in Brain of ASD Patients

Background: Although autism is one of the most heritable neuropsychiatric disorders, its underlying genetic architecture is poorly understood with a contribution of both multiple rare structural variations and common genetic variants. To comprehensively examine the hypothesis that common variation is important in autism, we are studying the effects of dosage imbalance of genes associated to autism spectrum disorders (ASDs) in mouse models. We recently reported that SLC25A12 and MARK1 were associated to ASDs and were overexpressed in post-mortem frontal cortex (BA 42) of patients with ASDs (Lepagnol-Bestel et al., Mol. Psychiatry, 2008; Maussion et al., Human Molecular Genetics, 2008). Lintas et al. (Mol. Psychiatry, 2009) reported that PRKCB1 gene haplotypes were significantly associated to ASDs and PRKCB1 gene expression was reduced in post-mortem temporocortical regions of patients with ASDs. Currently, we are studying the effect of dosage imbalance of SLC25A12, MARK1 and PRKCB1 in mouse models. Objectives: The goal of our study is to use these animal models to first understand the pathogenesis of ASD associated with specific gene dosage imbalance of SLC25A12, MARK1 and PRKCB1 and then to pharmacologically manipulate these model systems. Methods: Mouse transgenic mice were developed using standard techniques. For Slc25a12 and Mark1, we used a ~3.2 kb mouse Camk2a promoter and a short hairpin (sh) Prkcb1 construct with a CMV promoter. Results: Using in vitro cultures of mouse cortical neurons, we found that overexpression of Slc25A12 and Mark1 induced changes in dendrite length and dendritic spine morphology. The individual mouse models with dosage imbalance of Slc25a12, Mark1 and Prkcb1 are analyzed using biochemical,and neuropathological approaches. Characterization of dendritic spine morphology in these mice will be presented. Conclusions: Such mouse models with modified dosage of key genes associated to ASDs are expected to be instrumental in the characterization of intermediate phenotypes such as abnormal dendritic spine morphology and in the development of novel therapeutic strategies.